Furosemide (4-chloro-2-furfurylamino-5-sulphamoyl benzoic acid) is a drug with a diuretic action which acts at the renal level on the ascending limb of the loop of Henle. In addition to possessing a strong, rapid and short diuretic action, furosemide has a hemodynamic effect on the heart. Furosemide-induced diuresis begins within 20 minutes from oral dosing and stops in 4-5 hours.
This drug is used in the treatment of oedema of pulmonary, cardiac or hepatic origin as well as in the treatment of hypertension and in the chronic treatment of cardiac infarction.
However, use of furosemide in the foregoing treatments is often accompanied by adverse effects, the most important of which are the presence of a high diuresis peak and a marked drug absorption variability.
The diuresis peak causes most of the urinary excretion induced by furosemide to occur in the initial hours following administration, which causes weakness and fatigue symptoms particularly in elderly patients.
Absorption variability can be seen within the same patient after repeated doses as well as in different patients.
These adverse effects are traced to the fact that furosemide is absorbed and metabolized mostly at the gastric level and, to a lesser extent, at the level of the upper section of the intestine (Verhoeven J et al., Int. J. Pharm. 45, 65 (1988)) .
The formulations for the administration of furosemide presently on the market include fast-release tablets containing 20 to 500 mg of active ingredient, and injectable formulations containing 10 mg/ml. Controlled-release formulations are also known.
Generally, the fast-release formulations are used in the acute treatment of oedema, whereas controlled-release formulations are preferred in the chronic treatment of hypertension and cardiac infarction.
The controlled-release formulations were intended to reduce the diuresis peak while maintaining the quantity of urine excreted within 24 hours equal to that excreted with fast-release formulations. A controlled release formulation containing furosemide is disclosed in Ebihara et al. (Drug Res. 33, 163 (1983)); this formulation, however, does not have bioadhesive properties. In any case, the use of prior art controlled release formulations increases the above erratic absorption problem.
Patent application EP 277,925 describes an enteric-coated formulation with variable release, i.e. a formulation that has controlled release properties at pH 5-6, and immediate release properties at pH 7.4. This formulation attempts to avoid the diuresis peak by reducing release in the site of greater absorption and facilitating total drug release towards the end of the absorption window. However, this type of formulation eliminates gastric absorption, which, in the case of furosemide, results in a low drug bioavailability with a consequent reduced drug efficacy (Verhoeven J. et al., ibidem).
Patent EP 239,361 describes enteric-coated micro capsules containing furosemide, coated with an intermediate ethylcellulose film and an outer cellulose acetate phthalate film. However, considering the relatively slow release of furosemide from the microcapsules at pH 7.5 and considering that the transit of a solid dosage form through the upper section of the gastrointestinal tract takes about 6 hours (Harris D. et al., J. of Contr. Rel. 12, 45 (1990)), the release of this formulation is also likely to occur mostly outside the furosemide absorption window.
In addition to the above controlled-release formulations, a hydrophilic matrix containing furosemide is also known. This type of formulation releases about 94% of the drug content in 8 hours at pH 6.8 (Verhoeven J. et al., ibidem).
While more effective than a fast-release formulation (it achieves the same diuretic effects with a lower quantity of furosemide), the hydrophilic matrix formulation is incapable of avoiding a diuresis peak which appears to be comparable with that obtained with a fast-release dose.
As can be seen from the above, none of the solutions known to date can simultaneously solve the problems of erratic absorption and diuresis peak which accompany furosemide administration.
The use of bioadhesive pharmaceutical compositions to extend the residence in the host of controlled-release formulations is generally known. In particular, mucoadhesive materials have the property of adhering to mucous membranes for extended periods of time. In the gastrointestinal tract the residence of mucoadhesive materials extends at most to about 24 hours due to the daily replacement of the mucous membrane.
For instance, international patent application WO 85/02092 describes a pharmaceutical composition for the treatment of skin and mucous membranes which has bioadhesive properties. The bioadhesive agents used are fibrous, crosslinked and water-swelling (but not water-soluble) carboxy-functional polymers. The composition takes various dosage forms including an intimate mixture of the active ingredient with bioadhesive polymers, capsules, films or laminates.
Another example is disclosed in European patent EP 205,282 which describes a controlled-release pharmaceutical composition containing cellulose, capable of adhering to mucous membranes. This composition, in a solid dosage form and suitable for oral or nasal administration, consists of granules coated with mucoadhesive cellulose. The granules contain the active ingredient, a long-chain aliphatic alcohol and a water-soluble hydrous hydroxyalkylcellulose used both as a granule ingredient and as an extragranular ingredient.
A third example is disclosed in the U.S. Pat. No. 4,226,848, which describes an administration method employing a bioadhesive pharmaceutical composition. The composition contains a bioadhesive polymer matrix with the active ingredient dispersed within it which adheres to the oral or nasal cavities. In this case the bioadhesive matrix is made up of both a cellulose ether and a homopolymer or copolymer of acrylic acid.
It should be noted that none of the above-mentioned patents/applications discloses any formulation for the controlled release of furosemide.
Copending commonly assigned U.S. patent application Ser. No. 07/832,229 now abandoned discloses controlled release compositions with mucoadhesive properties comprising microunits with a controlled-release (non mucoadhesive) core containing the active ingredient and coated with a mucoadhesive. The mucoadhesive coating is selected to confer to the composition predetermined mucoadhesive characteristics and the core excipients are selected to produce a predetermined release profile for the active ingredient. This arrangement permits to control bioadhesive characteristics separately from release control characteristics, i.e. optimization of the former does not interfere with optimization of the latter.
Furosemide is mentioned as one of the active ingredients which can be administered by compositions of the prior copending application. However, this application does not take into consideration the additional technical problems of lowering diuresis peak and avoiding the erratic absorption which is typical of the dosage forms for this drug.
It has now surprisingly been found that, if the microunits for the controlled release of furosemide which are coated with mucoadhesive polymers are formulated as microgranules, so that the excipients used for granulation have an HLB (Hydrophilic Lipophilic Balance) lower than 8, a pharmaceutical composition for the controlled release of furosemide is obtained which is particularly effective in correcting erratic drug absorption and, therefore, substantially reducing therapeutic response variability in a host treated with furosemide. The full range of HLB values is from 1 to 50.
At the same time, this composition also limits the diuresis peak which normally follows drug administration, so that a formulation is obtained which is particularly suitable to be used in chronic administration of furosemide.